Cytomegalovirus is a frequent pathogen in humans and is usually associated with asymptomatic primary infection, followed by a state of viral persistence or latency. In patients with congenital or acquired immune deficiencies and those undergoing solid organ or bone marrow transplantation, primary CMV infection and reactivation of persistent CMV have frequently been associated with life-threatening invasive visceral disease.
Reactivation of the latent human herpes virus, Cytomegalovirus (CMV) post allogeneic haematopoietic stem cell transplantation (Allo-HSCT) can result in significant morbidity and mortality unless treated promptly. Anti-viral therapy is usually effective, but has serious side effects, such as myelosuppression (Ganciclovir™) or nephrotoxicity (Foscarnet™).
Cellular immunotherapy for CMV has been tested in Phase I/II trials in the UK and Europe. In these trials CMV-specific T cells were isolated from the peripheral blood of CMV seropositive donors and re-infused into recipients following CMV reactivation resulting in sustained anti-viral responses. Post-transplant recovery of CD8+ CMV-specific cytotoxic T-cells (CTL) abrogates the development of CMV-related disease. An advantage of cellular therapy for CMV reactivation is the transfer of immunological memory, which can reduce the number of subsequent reactivations.
Increasing numbers of highly immunosuppressive (or T cell depleted) reduced intensity conditioning Allo-HSCTs are being performed in the UK. Such approaches reduce the toxicity of transplantation in older patients with more co-morbidities. There are therefore more patients at risk of CMV reactivation post Allo-HSCT. Further, as these patients are older and have additional co-morbidities, making them less tolerant of currently available anti-viral drug therapy.
As approximately 50% of adult individuals have been previously infected with CMV, there are significant numbers of CMV ‘mismatched’ Allo-HSCT performed, where the donor is CMV seronegative and the recipient CMV seropositive. Transplant recipients with CMV seronegative donors do not benefit from cellular immunotherapy due to the lack of CMV-specific memory T cells. Such patients are therefore seriously at risk from complications arising from reactivation of latent CMV. At present, there is no reliable strategy to isolate virus specific T cells from uninfected naïve individuals, as the precursor frequency is low or absent and the in vitro priming of T-cell responses is inefficient.
There is thus a need for alternative methods to treat or prevent CMV disease, in particular reactivation of latent CMV post Allo-HSCT. There is also a need for an alternative source of CMV-specific T cells for cellular immunotherapy.